ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1427C>G (p.Pro476Arg)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV003461885 SCV004196280 uncertain significance Lynch syndrome 1 2023-08-31 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004011326 SCV004833341 uncertain significance Lynch syndrome 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 476 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV004364782 SCV005033217 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-28 criteria provided, single submitter clinical testing The p.P476R variant (also known as c.1427C>G), located in coding exon 9 of the MSH2 gene, results from a C to G substitution at nucleotide position 1427. The proline at codon 476 is replaced by arginine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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